Paxalisib

synthetischeStumpf et al. at Genentech Inc. (Roche group) developed an efficient multikilogram process to synthesize the brain penetrant PI3K inhibitor, GDC\0084, a potential drug candidate for the treatment of several brain cancers. An efficient Suzuki coupling reaction between a chloropyrimidine and an arylboronic ester using a palladium catalyst at low loading was reported. The optimized conditions were demonstrated on 6.75 kg of a chloropyrimidine intermediate, providing 7.49 kg of crude GDC\0084 (94% yield, 99.4% HPLC purity). Using the commercially available XPhos Pd G2 catalyst, instead of the usual PdCl2(dppf)·CH2Cl2 catalyst, it was possible to reduce the catalyst loading from 2 to 0.5 mol%. A final scavenging/recrystallization combination from Si\Thiol (a solid\supported resin) and acetic acid/water provided the crude GDC\0084 with the required purity and polymorphic form (off\white solid, 6.41 kg, 83% yield, 99.7% HPLC purity). Genentech’s route to GDC\0084 employing a pivotal Suzuki reaction.